PROJECT 2 ? SUMMARY Atypical, rapid early brain enlargement is a distinct neurophenotype that is observed in 15% of males with autism spectrum disorder (ASD). This phenotype has been labeled ?autism with disproportionate megalencephaly? (ASD-DM) because head and brain growth is disproportionate to height. Evidence from the UC Davis MIND Institute Autism Phenome Project suggests that a higher proportion of children with ASD-DM are minimally verbal at 3 years of age. By 5 years of age, children with this phenotype have made fewer gains in IQ than their counterparts with ASD and normal brain size. At school age, a higher proportion of ASD-DM have IQs in the range of intellectual disability. A short-term goal of this project is to confirm that ASD-DM have a poorer prognosis than other children with ASD. The long-term objective is to fully understand the cognitive processes and neural systems underlying these deficits so that targeted interventions can be developed to improve the prognosis of children with this phenotype. To accomplish these objectives, a new cohort of 2-3.5-year old children will be recruited with aid from the Recruitment and Retention Core. Four groups, ASD with normal brain size (ASD-N), ASD with disproportionate megalencephaly (ASD-DM) and typical development (TD) with normal or enlarged brain sizes will be evaluated. Children will be assessed longitudinally at two time points, once at study entry (2- 3.5 years of age) with a follow up visit two years later (4-5.5 years of age). In the first aim, a comprehensive behavioral evaluation that includes both standardized assessments and well-validated eye-tracking tasks that test specific cognitive processes of attention, memory, and language will be conducted. The eye-tracking tasks are expected to be more sensitive to subtle phenotypic differences than standardized measures and could guide development of targeted interventions. In the second and third aims, further evaluation of the neural underpinnings of the disproportionate megalencephaly phenotype will be carried out. Structural and functional MRI and auditory event-related potentials will be utilized to interrogate the neural basis of the impairments observed in this phenotype with emphasis on neural systems involved in attention, language, and memory. Identifying the neural systems that are involved in the behavioral deficits will provide clues not only to underlying etiologies, but will also provide neural targets that could be used as biomarkers for measuring treatment response in future studies. Participants in Project 2 will be invited to participate in Project 3, which aims to generate induced pluripotent stem cells (iPSCs) in order to investigate cellular mechanisms underlying megalencephaly in ASD. The Data Management and Statistics Core will manage data from both projects and will facilitate inter-project analyses. Accomplishing these aims will enable the research team to develop targeted interventions for this clinically meaningful phenotype that is present early in development and is easily identifiable in the first years of life.